1. Field of the Invention
The present invention relates to novel ((3,4,5,6-tetrahydro-2H-pyran-2-yl)methoxy)oxabicycloalkane derivatives, their use for controlling plant growth and as herbicides and to herbicidal and plant growth regulating compositions containing these novel derivatives.
2. Summary of the Invention
The present invention is directed to novel ((3,4,5,6-tetrahydro-2H-pyran-2-yl)methoxy)oxabicycloalkanes of the formula 1 ##STR2## wherein X is a single bond or --C(CH.sub.3).sub.2, Y is a single bond or --CH.sub.2 -- with the proviso that both X and Y are not a single bond; Z is H, or an alkyl group containing 1 to 4carbon atoms; each R independently is a hydrogen atom, a hydroxy group, an oxo group, a methylene group, or an alkyl or alkoxy group in which the alkyl portion contains from 1 to 6 carbon atoms or one pair of adjacent R groups form a carbon-carbon bond; and R.sup.1 is a hydrogen atom or an alkyl group containing 1 to 6 carbon atoms. The compounds are useful as plant growth regulators or herbicides and intermediates therefor.
Non-limiting embodiments of the compounds of formula 1 of the present invention include
6-((3,4,5,6-tetrahydro-2H-pyran-2-yl)methoxy)-1,3,3-trimethyl-2-oxabicyclo[ 2.2.2]octane, PA0 6-((3,4,5,6-tetrahydro-2H-pyran-2-yl)methoxy)-1,3,3-trimethyl-4-ethyl-2-oxa bicyclo[2.2.2]octane, PA0 2-((3,4,5,6-tetrahydro-2H-pyran-2-yl)methoxy-1-methyl-4-ethyl-7-oxabicyclo[ 2.2.1]heptane, PA0 2-((3,4,5,6-tetrahydro-2H-pyran-2-yl)methoxy)-1-methyl-7-oxabicyclo[2.2.1]h eptane, PA0 2-((3,4,5,6-tetrahydro-2H-pyran-2-yl)methoxy)-1-methyl-4-(1-methylethyl)-7- oxabicyclo[2.2.1]heptane, PA0 6-((3,4,5,6-tetrahydro-2H-pyran-2-yl)methoxy)-1,3,3-trimethyl-2-oxabicyclo[ 2.2.1]heptane, and the like.
The compounds of formula 1 exhibit geometrical and optical isomerism and can be prepared in geometrical and/or optically-active forms, and as racemates. The various individual optically and geometrical combinations of the materials of the invention usually have some different herbicidal properties. The present invention contemplates all the herbicidally active forms resulting from synthesis and deliberately created mixtures. Some of the ((3,4,5,6-tetrahydro-2H-pyran-2-yl)methyl ether compounds of the invention also have good photostability relative to the corresponding benzyl ethers as well as higher vapor pressure and increased hydrophilicity.
One embodiment of the present invention is directed to compounds of formula 1 of the invention wherein (1) X is a single bond, Y is --CH.sub.2 -- and Z is a hydrogen atom or a 1-methylethyl group or (2) X is --C(CH.sub.3).sub.2 --, and Z is a hydrogen atom. Preferably, when X is a single bond then Z is a 1-methylethyl group.
In another embodiment of the invention, each R independently is a hydrogen atom or an alkyl or an alkoxy group containing 1 or 2 carbon atoms and R.sup.1 is a hydrogen atom or methyl group. Preferably, each R independently is a hydrogen atom or a methyl group and R.sup.1 is a hydrogen atom.
The compounds of the invention described by formula 1 are prepared by treating an appropriately substituted oxabicycloalkanol with a compound of the formula ##STR3## in which X is a halogen atom, such as bromine, chlorine or iodine, or is a hydrocarbylsulfonyloxy group, e.g. a mesyloxy, tosyloxy group or the like, preferably in the presence of a strong base and an inert diluent. The strong base is suitably an alkali metal hydride, hydroxide or carbonate, including, for example, sodium hydride, sodium hydroxide, potassium carbonate and the like. Inert diluents are suitably organic solvents, such as ethers, aromatic hydrocarbons, chlorinated hydrocarbons and the like, including, for example, diethyl ether, tetrahydrofuran, dimethyl sulfoxide, toluene, methylene chloride and the like. The reaction is usually carried out under normal pressures and ambient temperatures. Suitable temperatures for the reaction are from about 0.degree. to about 120.degree. C., preferably from about 20.degree. to about 100.degree. C. The product ethers are recovered and isolated by conventional techniques.
The oxabicycloalkanol reactants are obtained generally by one or more of the following routes: directly by (a) epoxidation-cyclization of unsaturated cyclic alcohols, with or without isolation of epoxy alcohol intermediates; and indirectly by (b) Diels-Alder reactions of furans with dienophiles or (c) Birch reduction, etc.
Detailed routes are described below for the different ring systems.
In (a), the epoxidation-cyclization of unsaturated cyclic alcohols involves treatment in an inert solvent by an oxidizing agent followed by an acid. The alcohols are either (i) cycloalk-3-en-1-ols, or (ii) cycloalk-3-ene-1-methanols. The cycloalk-3-en-1-ols, useful for preparing compounds of the invention, are prepared from 1-oxaspiro(2.5)oct-5-enes: by reduction; by rearrangement and reduction of 1-oxaspiro(2.5) oct-5-enes; by reduction of cycloalk-3-en-1-ones; by treatment of cycloalk-3-en-1-ones with a Grignard reagent; by dealkylating or hydrolyzing, respectively, Diels-Alder adducts of vinyl ethers or esters prepared from dienes, such as isoprene, and vinyl ether or ester dienophiles in which the alpha-position of the vinyl group is substituted by alkyl, CO.sub.2 R.sup.8, or CON(R.sup.8).sub.2. The cycloalk-3-ene-1-methanols are (1) alpha-terpineol; (2) Diels-Alder adducts of allylic alcohols; or (3) products obtained from Diels-Alder adducts of alpha-beta unsaturated carbonyl compounds, such as acrylates, crotonates, acrolein or alkyl(methyl) vinyl ketone, by reduction or treatment with a Grignard reagent.
In (b), the Diels-Alder type adducts of furans with dienophiles may require vigorous reaction conditions, including high pressure and low temperature, for example, as described in Dauben, W. G. et al., J. Amer. Chem. Soc., 102, page 6894 (1980). When the dienophile is nitroethylene, the resulting product is hydrogenated, then oxidized to the ketone and reduced to the corresponding alcohol, e.g. by treatment with a hydride or metal. When this alcohol has the endo form, it can be epimerized with base or aluminum isopropoxide in the presence of a ketone to the corresponding exo alcohol.
Endo- and exo-oxabicycloalkanol intermediates can be separated by conventional methods, such as crystallization, chromatography and the like, and the geometric forms can be resolved by classical resolution methods to give a substantially pure single, optically-active isomer.
Non-limiting illustrations of the preparation of representative Compounds of the Invention follow.
In one embodiment, compounds having the formula I ##STR4## wherein Z has the above meaning can be prepared from 7-oxabicyclo[2.2.1]-heptan-2-ols obtained from (1) cyclohex-3-en-1-ols, by epoxidation-cyclization, or (2) Diels-Alder adducts of furans, such as 2,5-dimethylfuran, with dienophiles, such as nitroethylene, as described below.
The epoxidation of cyclohex-3-en-1-ols into the corresponding epoxy-alcohol is effected by action of an oxidizing agent, particularly a peroxide, such as m-chloroperbenzoic acid, peracetic acid, tert-butyl hydroperoxide (TBHP) or equivalent peroxide reagents. The oxidation to cis-alcohols with TBHP is conducted in the presence of an appropriate transition metal catalyst, e.g. vanadium. Preferably, the complex is an organic complex, for example, with beta-diketones, o-hydroxybenzaldehydes or o-hydroxybenzophenones and particularly with acetylacetone, for example, vanadium(IV) bis(2,4-pentanedionate)oxide is preferred. The reaction is suitably conducted in the presence of an inert solvent such as chlorinated hydrocarbons, ethers, hydrocarbons or the like. Suitable chlorinated hydrocarbons contain from 1 to 4 chlorine atoms in combination with an alkane chain containing from 1 to 4 carbon atoms or a benzene ring, for example, carbon tetrachloride, chloroform, dichloromethane, chlorobenzene and 1,2- or 1,3-dichlorobenzene and the like. Ethers are generally those containing from 4 to 6 carbon, for example, diethyl ether, methyl tert-butyl ether and diisopropyl ether. Tetrahydrofuran and dioxane are also useful. Suitable alkanes contain from 5 to 10 carbon atoms, for example, n-pentane, n-hexane, n-heptane, n-octane, n-nonane, n-decane and their isomers. Petroleum fractions rich in alkanes are also suitable. Petroleum ether is also suitable. Cyclohexane and methylcyclohexane are examples of useful cycloalkane solvents containing from 6 to 8 carbon atoms. Suitable aromatic hydrocarbon solvents contain from 6 to 10 carbon atoms, for example, benzene, toluene, o-, m-, and p-xylene, the trimethylbenzenes, p-ethyltoluene and the like. The reaction is conducted at temperatures conveniently in the range of from about -10.degree. C. to about 50.degree. C. or slightly above. Generally, the temperature is from about -5.degree. C. to about 40.degree. C., preferably from about 10.degree. C. to about 30.degree. C. The molar ratio of reactants can vary. Generally, a molar ratio of cyclohex-3-en-1-ol to oxidizing agent is from about 0.8 to about 1.0. The reaction is usually conducted by forming a mixture of the alcohol and oxidizing agent, preferably while agitating the reaction mixture, e.g. by stirring, and maintaining the desired reaction temperature. The resulting cis-epoxy-alcohol may be purified or converted without isolation into the 2-exo-hydroxy-7-oxabicyclo[2.2.1]-heptane by cyclization as described below.
The cyclization (ring closure) step surprisingly gave a high yield of product having the exo-hydroxy configuration in the resulting 7-oxabicyclo[2.2.1]heptan-2-ol. Many acids will catalyze this reaction, but a relatively strong acid such as sulfuric or sulfonic acids are suitable. Preferably, the acid is methanesulfonic acid or an arylsulfonic acid, such as p-toluenesulfonic, benzenesulfonic acids, or the like. Of these, p-toluenesulfonic acid is preferred. The reaction is suitably conducted by adding the acid to the epoxy-alcohol contained in an inert solvent of the type previously described for use in the preparation of the epoxy-alcohol. The reaction is conducted at a temperature conveniently in the range of from about 0.degree. C. to about 50.degree. C. or slightly above. Generally, the temperature is from about 5.degree. C. to about 40.degree. C., preferably from about 10.degree. C. to about 30.degree. C. The molar ratio of reactants can vary. Generally, the molar ratio of acid to epoxy-alcohol is from about 0.01 to about 0.10, and preferably from about 0.02 to about 0.04.
Thus, a 1,4-disubstituted-3-cyclohexen-1-ol is converted mainly to 2-exo-hydroxy-1,4-disubstituted-7-oxabicyclo[2.2.1]heptane by treating it with an oxidizing agent, such as tert-butyl hydroperoxide, or m-chloroperbenzoic acid, and then a strong acid, such as p-toluenesulfonic acid. Especially useful for obtaining a 2-exo-hydroxy-1,4-disubstituted-7-oxabicyclo[2.2.1]heptane is treatment of the corresponding 3-cyclohexen-1-ol with tert-butyl hydroperoxide and vanadium(IV) bis(2,4-pentanedionate)oxide as catalyst in methylene chloride followed by treatment of the intermediate epoxide, preferably in situ, with a sulfonic acid, particularly p-toluenesulfonic acid. Also, acid present during the epoxidation step produces the desired product.
The epoxidation-cyclization is disclosed and claimed in co-pending U.S. patent application Ser. No. 331,095, filed Dec. 16, 1981, and Ser. No. 414,548, filed Sept. 8, 1982, both abandoned and in Ser. No. 559,512, filed Dec. 8, 1983.
In situations where the endo form is desired, it can be obtained by oxidation of the 2-exo-hydroxy compound to the corresponding ketone followed by reduction of the ketone with sodium borohydride.
The 3-cyclohexen-1-ols useful for the preparation of Compound I can also be synthesized as described below or obtained from natural source (which offer the advantage of optically-active materials).
(a) where Z is 1-methylethyl, the starting compound is terpinen-4-ol, which occurs naturally. Terpinen-4-ol is converted to 2-exo-hydroxy-1-methyl-4-(1-methylethyl)-7-oxabicyclo[2.2.1]heptane by treatment with an oxidizing agent, for example, a peroxide such as m-chloroperbenzoic acid, peracetic acid or tert-butyl hydroperoxide, in an inert solvent. The optical configuration of terpinen-4-ol is retained in the reaction. Thus, (.+-.), (-) or (+) 2-exo-hydroxy-1-methyl-4-(1-methylethyl)-7-oxabicyclo[2.2.1]heptane can be obtained. 2-endo-Hydroxy-1-methyl-4-(1-methylethyl)-7-oxabicyclo[2.2.1]heptane is known from Garside et al., J. Chem. Soc., page 716-721 (1969). 2-exo- and endo-Hydroxy-1-methyl-4-(1-methylethyl)-7-oxabicyclo[2.2.1]heptanes are converted to the ethers of the invention as described above. Although terpinen-4-ol occurs in nature in optically active and racemic forms, it can also be prepared by epoxidation of terpinolene, e.g. with peracetic acid in methylene chloride, followed by reduction of the epoxide, e.g. with sodium diethylaluminum hydride in tetrahydrofuran.
(b) Preparation of 3-cyclohexen-1-ols can be effected from p-substituted phenols in which the substituent group corresponds to methyl in the formula I of the invention by procedures of the literature for the Birch-type reduction of derivatives of benzene, many of which are detailed in Rodd's Chemistry of Carbon Compounds, Second Edition, Vol. II, Part B, pages 1-4 (1968). In an example, para-cresol is first methylated to protect the hydroxy group yielding the corresponding p-methylanisole. This p-methylanisole is treated with a reducing agent such as lithium-ammonia or sodium-ammonia and the resulting product is hydrolyzed to yield the corresponding 4-methyl-3-cyclohexen-1-one. Treatment of this ketone with an appropriate organometallic (Grignard) reagent, ZMgBr or ZLi in which Z corresponds to that in the formula I of the invention and is alkyl, e.g. at 20.degree.-60.degree. C. in the presence of anhydrous ethers, yields the desired 1,4-disubstituted-3-cyclohexen-1-ol intermediate. The 4-methyl-3-cyclohexen-1-one can also be reduced, e.g. by hydrides, to the corresponding 3-cyclohexen-1-ol unsubstituted in position-1.
The 2-hydroxy-7-oxabicyclo[2.2.1]heptanes useful as precursors of compounds of the invention can also be prepared from Diels-Alder adducts of suitably-substituted furans, as dienes, and dienophiles. For example, 2,5-dimethylfuran adds readily to nitroethylene to give 1,4-dimethyl-2-nitrobicyclo[2.2.1]hept-5-ene. Similar adducts can be prepared from 2,5-dialkylfurans and dienophiles such as acrolein and acrylate esters. ##STR5## Severe reaction conditions including low temperature and high pressure may be required for some Diels-Alder reactions of substituted furans, for example, as described in Dauben, W. G. et al., J. Am. Chem. Soc., 102, page 6894 (1980). Hydrogenation and treatment of the nitro compound with a strong base such as potassium hydroxide, followed by an oxidizing agent, such as potassium permanganate, singlet oxygen, aqueous TiCl.sub.3, tert-butyl hydroperoxide in the presence of vanadium(IV) bis(2,4-pentanedionate)oxide or the like, affords the 1,4-disubstituted bicyclo[2.2.1]heptan-2-one. Reduction with a hydride or metal converts the ketone to the desired 2-hydroxybicyclo[2.2.1]heptane useful for preparation of compounds of the invention by aralkylation. Where the hydroxy group is in the endo orientation, epimerization to the more desirable 2-exo-hydroxy stereoisomer can be effected by treatment with a base, such as sodium hydroxide, or aluminum alkoxide in the presence of a ketone, preferably the corresponding ketone.
The materials of formula I that have the RCH.sub.2 O group (in which R is e.g. a (3,4,5,6-tetrahydro-2H-pyran-2-yl) group exo (formula Ia below) with respect to the oxygen-containing bridge are usually more herbicidally active than the endo form (formula Ib below) or the exo-endo mixture and are preferred. ##STR6##
The compounds of formula Ia and Ib have the 1S absolute configuration shown above. Such compounds of the subclass of formula Ia of the invention that correspond in configuration are preferred.
When an isomer or a mixture of isomers other than racemic mixtures is used substantially free of all other possible isomers, they are usually at least about 70% pure, although a purity above about 80%is preferable and a purity above about 95% is highly desirable. This invention contemplates all of the herbicidally active isomers, as well as any mixtures of isomers resulting from the synthesis methods used, and deliberately created mixtures.
In another embodiment of the invention, the compounds having the formula II ##STR7## wherein Z has the above meaning, can be prepared from 2-oxabicyclo[2.2.2]heptan-6-ols, made from (1) terpenes, such as alpha-terpineol or (2) Diels-Alder adducts of suitably substituted butadienes and dienophiles containing an oxygen function, as illustrated below. For example, (1) the compound is obtained from naturally occuring terpenes. Most elementarily, alpha-pinene is treated with aqueous acid to form alpha-terpineol, itself a naturally occuring material. alpha-Terpineol, either in racemic form or completely or partially optically active form, is oxidized, for example, with a peroxide such as hydrogen peroxide or m-chloroperbenzoic acid in a suitable solvent like methylene chloride, to yield a major amount of 1,3,3-trimethyl-2-oxabicyclo[2.2.2]octan-6-exo-ol. Oxidation of this alcohol, e.g. with N-bromoacetamide in aqueous acetone at 5.degree. C., gives 1,3,3-trimethyl-2-oxabicyclo[2.2.2]octan-6-one. Subsequent reduction of this ketone, for example with sodium borohydride in tert-butanol, yields a mixture of alcohols predominant in the endo isomer. Conversion to the ether of formula II of the Invention follows the earlier described procedures with retention of configuration.
(2) Diels-Alder adducts are formed from suitable, readily available dienophiles including an acrylate ester, acrolein, methacrolein, methyl vinyl ketone, allyl alcohol, a crotonate ester and the like. The diene component is isoprene, 2,3-dimethylbutadiene and the like. For example, the Diels-Alder adducts IIa are prepared by treating the portion of the compound of formula IIa above the dotted line ##STR8## with a dienophile (methyl acrylate) corresponding to the portion of the compound of formula IIa below the dotted line. Many such reactions are detailed in Rodd's Chemistry of Carbon Compounds, Second Edition, Vol II, Part B, pages 5-6 (1968). Treatment of IIa with the appropriate Grignard reagent (e.g. methyl magnesium bromide, ethyl magnesium bromide or the like) gives an alpha,alpha,4-trimethyl-cyclohexene-1-methanol of formula IIb below. ##STR9##
Alcohol IIb is oxidized, for example, with a peroxide, such as hydrogen peroxide or m-chloroperbenzoic acid, in a suitable solvent, such as methylene chloride, preferably in the presence of a strong acid, to yield a major amount of 1,3,3-trialkyl-2-oxabicyclo[2.2.2]octan-6-exo-ol. This exo form can be converted, if desired, into an endo-rich or substantially pure endo form. First, oxidation to the corresponding ketone, 1,3,3-trialkyl-2-oxabicyclo[2.2.2]octan-6-one, is effected with a suitable oxidizing agent. For example, the exo form is combined with oxalyl chloride and dimethyl sulfoxide in methylene chloride followed by addition of triethylamine. Then, the resulting ketone is converted into the endo-alcohol by reduction. For example, the ketone in a mixture of dimethoxyethane and tert-butanol is treated with sodium borohydride. Classical resolution can be applied to the 1,3,3-trialkyl-2-oxabicyclo[2.2.2]octan-6-ols to give substantially pure individual optical forms. The 1,3,3-trialkyl-2-oxabicyclo[2.2.2]octan-6-ols are converted into the desired ethers of the Invention, with retention of configuration, by treatment with a tetrahydrofuran-2-ylmethyl halide or sulfonate in which X is a halogen atom or hydrocarbylsulfonyloxy group, such as chlorine, mesyloxy or tolyloxy. This reaction is carried out, preferably in the presence of a base, such as sodium hydride, and, if desired, an inert solvent, such as N,N-dimethylacetamide, N,N-dimethylformamide, benzene, toluene or the like. The compounds of the invention can be recovered and purified by conventional techniques.
The materials of formula II that have the RCH.sub.2 O group (in which R is, e.g. a (3,4,5,6-tetrahydro-2H-pyran-2-yl) group endo (formula IIc below) are usually more herbicidally active than the exo form (formula IId below) or the endo-exo mixture and are preferred. ##STR10## The compounds of formula IIc and IId have the 1S absolute configuration shown above. Such compounds of the subclass of formula IIc of the invention that correspond in configuration are preferred. When an isomer or a mixture of isomers other than a racemic mixture is used substantially free of all other possible isomers, they are usually about 70% pure, although a purity above about 80% is preferable and a purity above about 95% is highly desirable. This invention contemplates all of the herbicidally active isomers, as well as any mixtures resulting from the synthesis methods used, and deliberately created mixtures.
In another embodiment of the invention, the compounds having the formula III ##STR11## in which R and R.sup.1 have the above meanings, can be prepared by condensation of 1,4-dibromo-2-methyl-2-butene with an alkyl acetoacetate, in the presence of base, followed by thermolysis of the isopropenyl acetyl cyclopropanecarboxylate intermediate to a cyclopentene carboxylate, which is hydrolyzed and decarboxylated to the corresponding ketone. Treatment of the ketone with a Grignard reagent, methyl magnesium bromide, yields the corresponding alcohol derivative. This alcohol is epoxidized and cyclized to an exo-2-oxabicyclo[2.2.1]heptan-6-ol. This exo-alcohol can be oxidized to the corresponding ketone followed by reduction to a corresponding endo-2-oxabicyclo[2.2.1]heptan-6-ol as described for the compounds of formula IIp above. The alcohol is treated with a tetrahydropyran-2-ylmethyl halide or sulfonate to yield the desired ether IIIp. An example of one alternative method is the condensation of a 1,4-dibromo-2-methyl-2-butene with a malonic acid dialkyl ester, again using base, followed by thermolysis. The resulting cyclopentene derivative is treated with, e.g., sodium chloride in dimethyl sulfoxide to eliminate one of the ester functional groups. Treatment of the resulting mono ester with the Grignard reagent, methyl magnesium bromide, yields the alcohol derivative previously described in the first methodology. See, also, Spurlock et al., Chemical Abstracts, 76:153024e (1972) for preparation of a 2-oxabicyclo[2.2.1]heptan-6-ol.
The materials of formula III that have the RCH.sub.2 O group (in which R is, e.g. (3,4,5,6-tetrahydro-2H-pyran-2-yl) endo (formula IIId below) are usually more herbicidally active than the exo form (formula IIIc below) or the endo-exo mixture and are preferred. ##STR12## These compounds of formula IIIc and IIId have the 1S absolute configuration shown above. Such compounds of the formula IIId of the invention are preferred. When an isomer or a mixture of isomers other than a racemic mixture is used substantially free of all other possible isomers, they are usually about 70% pure, although purity above 80% is preferred and a purity above about 95% is highly desirable. This invention contemplates all of the herbicidally active isomers, as well as any mixtures resulting from the synthesis methods used, and deliberately created mixtures.
The (3,4,5,6-tetrahydro-2H-pyran-2-yl)methanol derivatives R--CH.sub.2 X in which X is a halogen atom, or hydrocarbylsulfonyloxy group and R is the 2H-pyran moiety defined above in formula 1 are generally known in the art and are readily prepared from the (3,4,5,6-tetrahydro-2H-pyran-2-yl)methanols, by conventional methods known in the art for preparing halides and sulfonates of alcohols. For example, the tosylate is described in R. J. Palmer et al., J. Amer. Chem. Soc., 102 (27) pages 7888-92 (1980) as well as its preparation. The (3,4,5,6-tetrahydro-2H-pyran-2-yl)methanols are known materials or can be prepared by literature methods including application of the methods of G. Buchi and J. E. Powell, J. Amer. Chem. Soc., 92, 3126 (1970); E. L. Eliel, M. Manoharan, K. M. Pietrusiewicz, K. D. Hargrave, Org. Magn. Res., 21, 94 (1983); E. L. Eliel, K. D. Hargrave, K. M. Pietrusiewicz, M. Manoharan, J. Amer. Chem. Soc., 104, 3635 (1982) and J. Jurczak and M. Tkacz, J. Org. Chem., 44, 3347 (1979). For example, the alkylated (3,4,5,6-tetrahydro-2H-pyran-2-yl)methanols and the (3,4-dihydro-2H-pyran-2-yl)methanols are prepared by forming adducts from simple, readily available, unsaturated and oxygenated conventional materials, e.g. acrolein, methyl vinyl ketone, isoprene, diethyl oxomalonate and the like. Thus, known acrolein dimer, methyl vinyl ketone dimer and isoprene diethyl oxomalonate adduct and the like, are useful pyranyl derivative intermediates containing a functional carbonyl, or carboxylic acid or ester group which is further derivatized by one or more conventional techniques of, e.g. (a) imine formation, for example, using t-butylamine in an inert solvent followed by a Grignard reagent and methyl iodide; (b) carbonyl formation, for example, by treating an imine with aqueous acetic acid; (c) decarboxylation, for example, by treating a carboxylic acid ester substituent with hydrochloric acid; (d) reduction, for example, of a ring double bond by hydrogenation in the presence of a noble metal catalyst such as Pt/C, reduction of a carbonyl substituent to hydroxymethyl with sodium borohydride or reduction of a carboxylic acid substituent (optionally from hydrolysis of the corresponding ester) with lithium aluminum hydride, to obtain the desired 2H-pyran-2-methanol intermediate, which for convenience, is usually converted to their corresponding alkyl or aralkyl sulfonyloxy derivative for reaction with the desired oxabicycloalkanol to form an ether of formula 1.
A dihydro-2H-pyran-2-ylmethoxy ether of Formula 1 is an especially useful intermediate to the ethers of formula 1 in which R is, e.g. hydroxy, oxo, methylene, alkyl or alkoxy by use of conventional synthesis techniques. For example, (3,4-dihydro-2H-pyran-2-yl)methanol ether is treated with, e.g. borane in tetrahydrofuran followed by hydrogen peroxide and sodium hydroxide, to give the corresponding (3,4,5,6-tetrahydro-5-hydroxy-2H-pyran-2-yl)methanol ether. This hydroxy ether is treated with, e.g. oxalyl chloride in dimethyl sulfoxide, to obtain the corresponding (3,4,5,6-tetrahydro-2H-5-oxo-pyran-2-yl)methanol ether. This oxo ether is treated with, e.g. methyl triphenyl phosphonium bromide, to obtain the corresponding (3,4,5,6-tetrahydro-2H-5-methylene-pyran-2-yl)methanol ether. This ether is treated with, e.g. hydrogen in the presence of platinum oxide and ethyl acetate, to give the corresponding (3,4,5,6-tetrahydro-2H-5-methoxypyran-2-yl)methanol ether.